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Pretibial Myxedema


Pretibial myxedema, which is also known as infiltrative dermopathy, is a thyroid dermopathy characterized by the development of abnormallly thick and waxy skin over the shin. It occurs almost exclusively secondary to Grave's disease, an autoimmune cause of hyperthyroidism.


Pretibial myxedema occurs most commonly after 1 to 2 years of onset of Grave's disease, however, it could occur much later or earlier. The natural course of the disease is not clearly understood, there are studies whic indicate that complete remission occurs in 10 - 26% of patients, while partial remission occurs in 24% of patients. Pretibial myxedema without Grave's disease is very uncommon, therefore, pretibial myxedema without opthalmopathy and acropachy is rare [10].

The characeristic feature in pretibial myxedema is the presence of thickened and indurated skin with papules and nodules with clear margins. These lesions may be pigmented and pruritic, and usually have an orange-peel appearance.

The commonest sites of pretibial myxedema is the lower legs, particularly, the pretibial areas and the dorsal aspect of the foot. The lesions rarely affect the upper extremities and the face.

Clinical features progress for several months, before reaching a climax, and in some cases, regress spontaneously. Occasionally, the features may progressively affect the hands and feet.

Clinical features of hyperthyroidism such as finger clubbing, and arthropathic changes involving the bones of the hands and feet also occur. This osteoathropathy is called thyroid acropachy.

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The diagnosis of pretibial myxedema is usually made on clinical grounds: from physical examination of the skin lesions and a history of chronic hyperthyroidism, Grave's disease, and thyroid ophthalmopathy.

However, laboratory investigations may be ordered to support the diagnosis. Thyrotropin levels are usually abnormally high or low, depending on the treatment status of the underlying Grave's disease. Furthermore, LATs levels may be elevated in approximately half of the cases of pretibial myxedema.

The appearnce of the skin in pretibial myxedema may be similar to the skin appearance and lesions in chronic dermatitis, cutaneous mucinosis, and chronic lymphatic and venous obstruction, all of which can be excluded with a punch biopsy of the skin.

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Usually, the dermopathy in pretibial myxedema only causes cosmetic problems, however, much severe forms may case serious limb enlargement and restriction of movement.

Topical or intralesional corticosteroids are the mainsatay of treatment of pretibial myxedema. Systemic use is best avoided to forestall adverse effects of the drug. Effective combinations available include pentoxyfylline and clobastol propionate ointment [11] [12] and pentoxyfylline and intralesional triamcinolone acetonide [13]. Corticosteroids are effective for mild to moderate cases and should be repeated until remission begins.

Other medical treatment which have been tried include cytotoxic drugs and plasmapheresis. However, these treatment options have not been proven to be effective.

Compression stockings which provide pressures of up to 40mmHg may be useful to reduce the limb swelling.

Promising treatment options include octreotide, an analog of somatostatin, and intravenous immunoglobulin (IVIG) given at high doses [14]. Research findings of reduction in the production of glycosaminoglycans by octreotide has provided a foundation for its experimental use and proposed effectiveness in the treatment pretibial myxedema. These results were noted in patients with refractory symptoms and who had high levels of IGF-1 receptors on fibroblasts. Some studies have reported success with octreotide injections administered weekly with patients acheiving complete resolution of symptoms for up to 15 months [15] [16]. However, not all patients treated with octreotide had complete remission [17].

Surgery is relatively contraindicated in pretibial myxedema because scarring aggravates the condition. Reports, however, have it that one patient with pretibial myxedema who had hard plaques in the pretibial area showed remarkable remission of symptoms after surgery with non-recurrence after up to a decade of surveillance [18].


Pretiabial myxedema is not associated with significant morbidity nor mortality. It persists for several months to years and often remits without any intervention. In an average of 50% of patients, complete remission of symptoms occur. In the rest 50% of patients, there is neither any clinical improvement nor remission.

A study showed a contrast phenomenon such that outcome was better in those who are untreated and the most severe cases occurred in patients who were receiving treatment.


Pretibial myxedema is a cutaneous disease which occurs almost exclusively in Grave's disease. The actual etiology of pretibial myxedema is not clearly known, however findings of a higher concentration of anti-TSH receptor autoantibodies in these individuals suggests that these antibodies may contribute to the pathogenesis of pretibial myxedema, however, a direct evidence of this is yet to be provided. Furthermore, the expression of TSH receptor protein in normal fibroblasts of the skin further suggests that TSH-receptor autoantibodies may be responsible for setting off the inflammatory response which stimulates the synthesis of glycosaminoglycans by the fibroblasts [1] [2].

Antibodies against insulin-like growth factors (IGF-1) receptor are also present in patients with grave's disease and has been identified as stimulants of synthesis of hyaluronic acid [3]. Certain cytokines including tumor necrotic factor alpha and gamma interferon are secreted by Th1 type T cells which are activated by TSH receptor antigen, these cytokines have also been found to induce glycosaminoglycans synthesis by fibroblasts [1] [2] [4].

The fact that TSH receptors are expressed in normal skin makes the presence of TSH receptor antibodies and antigen-specific T cells the hallmark of pretibial myxedema.

Pretibial myxedema is also common in patients who have undergone successful radioactive iodine thyroid treatment, thyroidectomy, or medical treatment for hyperthyroidism [5].


In the united states, pretibial myxedema has been found to occur in 0.5 to 4.3% of patients with Grave's disease. However, it has also been shown to occur in hashimoto's thyroiditis, primary hypothyroidism, and even euthyroid states.

Most cases of pretibial myxedema occur in old adults with a peak incidence in individuals aged 50 to 60. However, it may occur in children and young adults.

Pretibial myxedema occurs more commonly among women than men with a ratio of 3.5:1.

Pretibial myxedema is not associated with significant morbidity nor mortality. Cosmetic disfiguration is the main concern in pretibial myxedema.

Sex distribution
Age distribution


Pretibial myxedema results from deposition of hyaluronic acid formed by the fibroblasts into the dermis and subcutaneous tissue. The main pathophysiologic factor in pretibial myxedema is the excessive production of hyaluronic acid. In this disease, the plasma membranes of fibroblasts contain thyrotropin and thyrotropin receptor antibody binding sites. A certain immunoglobulin called long-acting thyroid stimulator (LATS) is present in the serum in almost all cases of pretibial myxedema and has been found to be autoantibodies to thyrotropin receptor [6].

A research published in 2006 suggested that the alteration in the percentage of the components of glycosaminoglycans, in addition to an increase in their concentrations may be responsible for pretibial myxedema. Based on some findings which reveal that glycosaminoglycan synthesis is reduced in hyperthyroid states and coupled with the fact that thyroid hormones modify metabolism of glycosaminoglycans by altering the metabolism of prostaglandin synthesis, some researches have suggested that prostaglandin degradation may be the main etiological factor in pretibial myxedema [7].

Cell mediated immunity via T cell surface receptors has been suggested to also play a role in the pathogenesis of pretibial myxedema [8]. Because pretibial myxedema always manifests on areas of the skin previously exposed to injury, trauma may also be implicated in local fibroblast stimulation.

A notable finding in Grave's disease is that the extrathyroid features occur in the orbits and skin, both of which contain fibroblasts which differ in phenotypic properties from fibroblasts found in other parts of the body.

Pretibial myxedema typically starts within 1 to 2 years of onset of Grave's disease. Typically, ophthalmopathy precedes dermopathy by 6 to12 months, while acropachy occurs after the dermopathy. Findings of ophthalmopathy, thyroid acropachy, and pretibial myxedema together occur in less than 1% of cases of Grave's disease [9].


Generally, thyroid ophthalmopathy and dermopathy can be prevented in the same way by controlling thyroid hormone concentrations and administering early local corticosteroid for minimal pretibial myxedema.

The most important risk factor for development and progression of Grave's opthalmopathy is cigarette smoking. Therefore smoking cessation can be employed as a strategy for primary, secondary, and tertiary prevention.


Pretibial myxedema is an autoimmune dermatological complication of Grave's disease. Myxedema is a term initially connoted to describe skin swelling in hypothyroidism. In myxedema, the skin appears tough with a waxy coating. Whereas this "original" myxedema is commonly seen in hypothyroidism, pretibial myxedema occurs in the hyperthyroid state in Grave's disease. The hypothyroidism-associated myxedema commonly affects the entire body and the face.

Pretidial myxedema appears similar to the original description of myxedema, but it affects mainly the lower legs and the dorsum of the feet.

The etiopathogenesis of pretibial myxedema is centered on the increased stimulation of the fibroblasts in the skin, which in turn, excessively produce glycosaminoglycans, particularly hyaluronic acid, which are components of the connective tissue ground substace and responsible for the dermopathy. The cause of this overstimulation is linked to the anti-thyroid antibodies which are found in graves disease. The resulting lesions are erythermatous and pruritic in the initial stages of the disease. The edema is usually nonpittng in pretibial myxedema. Pretibial myxedema almost always occurs with Grave's ophthalmopathy.

A diagnosis of pretibial myxedema is often clinical, being made on physical examination of the pretibial skin lesions coupled with a history of Grave's disease. However, laboratory investigations including serologic identification of the autoantibodies may be necessary.

Treatment involves control of hyperthyroidism and administration of topical or intralesional corticosteroid. Compression stockings may also be necessary. Surgery is relatively contraindicated as the scarifications from surgery may aggravate the skin lesions.

Patient Information


Pretibial myxedema is a skin disease which occurs in a thyroid disease called Grave's disease. It is characterized by thickness of the skin with a lot of rashes of various sizes, primarily affecting the lower legs and upper part of the feet. Spontaneous disappearance of the symptoms may be experienced by up to 50% of patients.


Pretibial myxedema occurs in Grave's disease, a disease in which the cells of the thyroid gland are destroyed by antibodies which target certain proteins in the thyroid tissue, leading to very high amounts of thyroid hormones in the blood. Therefore, this skin disease is considered to be caused by these antibodies. However, pretibial myxedema may also occur in persons who have been treated for hyperactive thyroid gland.


This disease is most common in individuals aged between 50 and 60 and it is more predominant in women. Not all patients with Grave's disease develop this disease, only about 4% of them do.


The central concept in the development of this disease is the increased production of a group of chemicals called glycosaminoglycans which are chemicals which make skin and other tissues tough. These chemicals are produced by certain cell types called fibroblasts which are overstimulated by the antibodies found in graves disease to cause pretibial myxedema.


Pretibial myxedema is not associated with significant illness, neither does it cause death. The only problem is the bad appearance it gives the skin and legs. The symptoms may eventually disappear on their own after a couple of years.


Pretibial myxedema presents with thickness of the skin with dark and itchy rashes on the lower legs which may spread to the upper surface of the feet and even the hands. In severe cases, the legs may be so enlarged taking the appearance of elephantiasis.

Other signs and symptoms of high thyroid hormone levels such as hardening and stiffening of the bones of the hands and feet may also be present. Pretibial myxedema almost always presents in Grave's disease and the characteristic eye bulge seen in Grave's disease is usually present.


Most times, doctors do not need laboratory tests to make a diagnosis of pretibial myxedema. The appearance and site of the skin problems in a patient with a history of Grave's disease and the characteristic eye bulge is all that's needed to make this diagnosis. However, laboratory tests may support the diagnosis. Blood tests to detect the antibodies may be necessary.

The skin appearance may be similar to what's found in certain other skin disease such as chronic dermatitis, so the doctor may take a small slice of the skin, in a procedure, called punch biopsy, to analyse and determine the correct disease.


Corticosteroid ointments applied on the skin or the solutions injected into the skin are the standard treatments of pretibial myxedema. However, there are other drugs being experimented on which show possible effectiveness in treating this disease. Surgery is not often considered in treating pretibial myxedema because the scars created during the surgery may worsen the disease.



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  3. Smith TJ, Hoa N. Immunoglobulins from patients with Graves' disease induce hyaluronan synthesis in their orbital fibroblasts through the self-antigen, insulin-like growth factor-I receptor. J Clin Endocrinol Metab 2004; 89:5076.
  4. Bahn RS, Heufelder AE. Pathogenesis of Graves' ophthalmopathy. N Engl J Med 1993; 329:1468.
  5. Verma S, Rongioletti F, Braun-Falco, Ruzicka T. Preradial myxedema in a euthyroid male: A distinct rarity. Dermatol Online J. 201315;19(4):9.
  6. Kamath C, Young S, Kabelis K, Sanders J, Adlan MA, Furmaniak J, et al. Thyrotrophin receptor antibody characteristics in a woman with long-standing Hashimoto's who developed Graves' disease and pretibial myxoedema. Clin Endocrinol (Oxf). 2012 Sep. 77(3):465-70.
  7. Komosinska-Vassev K, Winsz-Szczotka K, Olczyk K, Kozma EM. Alterations in serum glycosaminoglycan profiles in Graves' patients. Clin Chem Lab Med. 2006. 44(5):582-8.
  8. Heufelder AE, Bahn RS, Scriba PC. Analysis of T-cell antigen receptor variable region gene usage in patients with thyroid-related pretibial dermopathy. J Invest Dermatol. 1995 Sep. 105(3):372-8.
  9. Anderson CK, Miller OF. Triad of exophthalmos, pretibial myxedema and acropachy in a patient with Graves’ disease. J Am Acad Dermatol. 2003;48(6):970-972.
  10. Subramanyam S, Lohiya V, Stahl EJ. Pretibial Myxedema Without Ophthalmopathy: An Initial Presentation of Graves' Disease. Am J Med Sci. 2013 Mar 19.
  11. Pineda AM, Tianco EA, Tan JB, Casintahan FA, Beloso MB. Oral pentoxifylline and topical clobetasol propionate ointment in the treatment of pretibial myxoedema, with concomitant improvement of Graves' ophthalmopathy. J Eur Acad Dermatol Venereol. 2007 Nov. 21(10):1441-3.
  12. Türke B, Balázs C. [Treatment of pretibial myxoedema with pentoxifylline]. Orv Hetil. 2012 Oct 28. 153(43):1719-22.
  13. Engin B, Gümüsel M, Ozdemir M, Cakir M. Successful combined pentoxifylline and intralesional triamcinolone acetonide treatment of severe pretibial myxedema. Dermatol Online J. 2007 May 1. 13(2):16.
  14. Antonelli A, Navarranne A, Palla R, Alberti B, Saracino A, Mestre C, et al. Pretibial myxedema and high-dose intravenous immunoglobulin treatment. Thyroid. 1994 Winter. 4(4):399-408.
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  16. Shinohara M, Hamasaki Y, Katayama I. Refractory pretibial myxoedema with response to intralesional insulin-like growth factor 1 antagonist (octreotide): downregulation of hyaluronic acid production by the lesional fibroblasts. Br J Dermatol. 2000 Nov. 143(5):1083-6.
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Last updated: 2018-06-22 05:47